Patient-level analysis of the cost and variation in melatonin prescribing patterns in those under 18 in the North East of England.

Background: Melatonin is widely used to promote sleep in both normally developing children and adolescents and those with neurodevelopmental disorders. It has an evidence base as both hypnotic and chronobiotic although the optimum dose and timing remain unclear. There are now a wide variety of different preparations of melatonin both immediate and prolonged release.

Gestational Development of the Human Immune System.

Building an immune system is a monumental task critical to the survival of the fetus and newborn. A functional fetal immune system must complement the maternal immune system in handling in utero infection; abstain from damaging non-self-reactions that would compromise the materno-fetal interface; mobilize in response to infection and equip mucosal tissues for pathogen exposure at birth. There is growing appreciation that immune cells also have noncanonical roles in development and specifically may contribute to tissue morphogenesis.

Conjunctival epithelial cells resist productive SARS-CoV-2 infection.

Conjunctival epithelial cells, which express viral-entry receptors angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine type 2 (TMPRSS2), constitute the largest exposed epithelium of the ocular surface tissue and may represent a relevant viral-entry route. To address this question, we generated an organotypic air-liquid-interface model of conjunctival epithelium, composed of basal, suprabasal, and superficial epithelial cells, and fibroblasts, which could be maintained successfully up to day 75 of differentiation. Using single-cell RNA sequencing (RNA-seq), with complementary imaging and virological assays, we observed that while all conjunctival cell types were permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome expression, a productive infection did not ensue.

Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2.

The nasal epithelium is a plausible entry point for SARS-CoV-2, a site of pathogenesis and transmission, and may initiate the host response to SARS-CoV-2. Antiviral interferon (IFN) responses are critical to outcome of SARS-CoV-2. Yet little is known about the interaction between SARS-CoV-2 and innate immunity in this tissue.

Cystic fibrosis.

Cystic fibrosis is a monogenic disease considered to affect at least 100 000 people worldwide. Mutations in CFTR, the gene encoding the epithelial ion channel that normally transports chloride and bicarbonate, lead to impaired mucus hydration and clearance. Classical cystic fibrosis is thus characterised by chronic pulmonary infection and inflammation, pancreatic exocrine insufficiency, male infertility, and might include several comorbidities such as cystic fibrosis-related diabetes or cystic fibrosis liver disease.

Interferon regulatory factor 8 regulates expression of acid ceramidase and infection susceptibility in cystic fibrosis.

Most patients with cystic fibrosis (CF) suffer from acute and chronic pulmonary infections with bacterial pathogens, which often determine their life quality and expectancy. Previous studies have demonstrated a downregulation of the acid ceramidase in CF epithelial cells resulting in an increase of ceramide and a decrease of sphingosine. Sphingosine kills many bacterial pathogens, and the downregulation of sphingosine seems to determine the infection susceptibility of cystic fibrosis mice and patients.

Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study.

Background: The presence of co-morbidities, including underlying respiratory problems, has been identified as a risk factor for severe COVID-19 disease. Information on the clinical course of SARS-CoV-2 infection in children with cystic fibrosis (CF) is limited, yet vital to provide accurate advice for children with CF, their families, caregivers and clinical teams.

Methods: Cases of SARS-CoV-2 infection in children with CF aged less than 18 years were collated by the CF Registry Global Harmonization Group across 13 countries between 1 February and 7 August 2020.

Clinical and molecular characterization of the R751L-CFTR mutation.

Cystic fibrosis (CF) arises from mutations in the CF transmembrane conductance regulator () gene, resulting in progressive and life-limiting respiratory disease. R751L is a rare CFTR mutation that is poorly characterized. Our aims were to describe the clinical and molecular phenotypes associated with R751L.

Trends in nontuberculous mycobacteria infection in children and young people with cystic fibrosis.

Nontuberculous mycobacteria (NTM) infection is of growing concern in cystic fibrosis (CF). UK CF Registry data were analyzed from 2016 to 2018. Prevalence of infection stabilized in the pediatric age-group during this period but remained substantially higher than in 2010.

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis.

In cystic fibrosis the major cause of morbidity and mortality is lung disease characterized by inflammation and infection. The influence of sphingolipid metabolism is poorly understood with a lack of studies using human airway model systems. To investigate sphingolipid metabolism in cystic fibrosis and the effects of treatment with recombinant human acid ceramidase on inflammation and infection.

Real-Time, Semi-Automated Fluorescent Measurement of the Airway Surface Liquid pH of Primary Human Airway Epithelial Cells.

In recent years, the importance of mucosal surface pH in the airways has been highlighted by its ability to regulate airway surface liquid (ASL) hydration, mucus viscosity and activity of antimicrobial peptides, key parameters involved in innate defense of the lungs. This is of primary relevance in the field of chronic respiratory diseases such as cystic fibrosis (CF) where these parameters are dysregulated. While different groups have studied ASL pH both in vivo and in vitro, their methods report a relatively wide range of ASL pH values and even contradictory findings regarding any pH differences between non-CF and CF cells.

Ataluren in cystic fibrosis: development, clinical studies and where are we now?

Cystic fibrosis (CF) is one of the most common genetically-acquired life-limiting conditions worldwide. The underlying defect is dysfunction of the cystic fibrosis transmembrane-conductance regulator (CFTR) which leads to progressive lung disease and other multi-system effects. Around 10% of people with CF have a class I nonsense mutation that leads to production of shortened CFTR due to a premature termination codon (PTC).

CK2 is a key regulator of SLC4A2-mediated Cl/HCO exchange in human airway epithelia.

Transepithelial bicarbonate secretion by human airway submucosal glands and surface epithelial cells is crucial to maintain the pH-sensitive innate defence mechanisms of the lung. cAMP agonists stimulate HCO secretion via coordinated increases in basolateral HCO influx and accumulation, as well as CFTR-dependent HCO efflux at the luminal membrane of airway epithelial cells. Here, we investigated the regulation of a basolateral located, DIDS-sensitive, Cl/HCO exchanger, anion exchanger 2 (AE2; SLC4A2) which is postulated to act as an acid loader, and therefore potential regulator of HCO secretion, in human airway epithelial cells.

Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets.

Cystic fibrosis (CF) is a life-limiting disease characterised by recurrent respiratory infections, inflammation and lung damage. The volume and composition of the airway surface liquid (ASL) are important in maintaining ciliary function, mucociliary clearance and antimicrobial properties of the airway. In CF, these homeostatic mechanisms are impaired, leading to a dehydrated and acidic ASL.

Targeted therapies to improve CFTR function in cystic fibrosis.

Cystic fibrosis is the most common genetically determined, life-limiting disorder in populations of European ancestry. The genetic basis of cystic fibrosis is well established to be mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for an apical membrane chloride channel principally expressed by epithelial cells. Conventional approaches to cystic fibrosis care involve a heavy daily burden of supportive treatments to combat lung infection, help clear airway secretions and maintain nutritional status.

GvHD-associated cytokine polymorphisms do not associate with Omenn syndrome rather than T-B- SCID in patients with defects in RAG genes.

Recombinase activating genes 1/2 (RAG1/2) deficiency, critical to initiate gene rearrangement encoding lymphocyte receptors, causes T-B- severe combined immunodeficiency (SCID) and Omenn syndrome (OS), characterised by erythroderma, hepatosplenomegaly, lymphadenopathy, activated, clonal T cell expansions with restricted TCRVbeta family usage, and opportunistic infection. Many features of OS resemble graft-versus-host disease (GvHD). Frequency of GvHD-associated cytokine gene polymorphisms (CGPs) with OS was investigated to explain phenotypic differences between T-B- SCID and OS.